X-ray-contrast medium with a density of 0.8-1.1



United States Patent Ofi ice 3,368,944- Patented Feb. 13, 1968 3,368,944X lRAY-CQNTRAST MEDIUM WITH A DENSITY F 0.84.1 Stig .ltihs GustavSandman-k, Knut Wicksells Veg 19,

Lund, Sweden, and Ernst Helmcr Hagstam, 'luhorgsgatan 1B, Mahno, SwedenNo Drawing. iIontinuation-in-part of appiication Ser. No. 251,760, Jan.16, 1963. This application Feb. 9, 1965, Ser- No. 431,428 Claimspriority, application Sweden, Jan. 23, 1962, 723/62 7 Claims. (Cl.167-95) as they are of high density because of the addition of the heavyX-ray absorber.

The abdominal cavity is filled mainly with mobile organs of about thesame density as water and usually the density of these mobile organs isabout 1.03 to 1.06

g./cm. The contents of the gastro-intestinal tract are also of about thesame density. Pressure measurements have shown that the abdominal cavitybehaves like a closed cavity filled with water. Thus, with normalgastrointestinal contents the hydrostatic pressure acting on the insideand the outside of a given segment of the intestinal wall is about thesame.

The contrast media hitherto used for the X-ray examinations of thegastro-intestinal tract are of high density (about 1.4 to 2.0 g./cm. andtherefore the hydrostatic pressure within the gastro-intestinal tractwhen being filied with such a contrast medium is higher than thehydrostatic pressure within the abdominal cavity but outside thegastro-intestinal tract. This difference in pressure distorts thegastrointestinal tract with the result that the contrast medium cannotreadily pass through the gastrointestinal tract and possibly does notreach the parts of the stomach or intestine to be examined because theX-ray contrast medium sinks to those parts of the gastrointestinal tractwhich happen to be lowermost at the time of the examination. Thisdisadvantageous eifect may cause difliculties in examinations for e.g.hiatus hernia.

Thus there is a need for an X-ray contrast medium of about the samedensity as that of the abdominal organs so that the X-ray contrastmedium can pass through the gastro-intestinal tract like ordinary foodin a physiologically correct way and independently of the patientsposture. Hitherto it has, however, not been possible to produce suchcontrast media and as far as we know priorart contrast media all are ofa density of at least 1.4 g./cm. which density cannot be reduced byknown methods.

An object of the invention is to provide an X-ray contrast medium havingsuch a density that it can pass through the gastro-intestinal tract likeordinary food in a physiologically correct way and independently of thepatients posture.

Another object of the invention is to provide an X-r'ay contrast mediumhaving a density of 0.8 to 1.1 g./cm.

Still another object of the invention is to provide an X-ray contrastmedium consisting of an X-ray absorber, a particulate resin foam, waterand a thickening agent,

the proportions of said components being such that the X-ray contrastmedium has a density of 0.8 to 1.1 g./cm.

A further object of the invention is to provide an X-ray contrast mediumcomprising a particulate, therapeutically acceptable resin foam, iodinechemically bonded to said resin foam, water 'and a non-toxic thickeningagent, the proportions of said components being such that the X-raycontrast medium has a density of 0.8 to 1.1 g./cm.

According to the invention, the X-ray contrast medium comprises an X-rayabsorber comprising a memberof the group consisting of barium sulphate,bismuth subcarbonate, thorium oxide and iodine, a particulate,therapeutically acceptable resin foam comprising a member of the groupconsisting of polystyrenes, polyethylenes and urea resins, water and anon-toxic thickening agent of the group consisting of thickeners ofseaweed origin, vegetable gums and water soluble cellulose esters, theproportions of said components being such that the X-ray contrast mediumhas a density of 0.8 to 1.1 g./cm.

The X-ray absorber is preferably homogeneously incorporated in the resinfoam and in this case it is possible to prevent the X-ray absorber fromcoming in direct contact with the contents of the gastro-intestinaltract. Thus, as an X-ray absorber one may use an element or a compoundthat is toxic per se.

The X-ray contrast medium according to the invention may be prepared bypreparing a thixotropic suspension of the X-ray absorber, e.g. bariumsulphate, water, a suitable amount of a carrier material comprisingparticulate therapeutically acceptable resin foam and a nontoxicthickening agent, the relative amounts of the said components being suchthat the final X-ray contrast medium has a density of 0.8 to 1.1 g./cm.

Another possibility of preparing the X-ray contrast medium according tothe invention is to melt the resin and incorporate the X-ray absorber bymixing it with the molten resin. The mixture may then be treated withair or gas, whereupon the mixture is allowed to set. The set material isground and sieved to the desired particle size. The particles are thenexpanded in a well known way by heating them for a short period to aboutC. so that the resin softens and the enclosed air or gas expands.Instead of melting the resin it is 'also possible to prepare a solutionof the resin in a suitable solvent e.g. ethyl acetate and to suspend theX-ray absorber in the solution. Next, the suspension is spread in a thinlayer and dried and then the dried material obtained is ground andsieved to the desired particle size. The particles are placed in asuitable fluid such as petroleum ether or pentane, for a period of e.g.12 hours. During this time the particles swell. Excess fluid is thensucked off and the swollen particles are stirred in water at 90 C.,thereby expanding.

The expanded particles prepared in either of the two above mentionedmethods from a molten mass or a solution of the thermoplastic resinmaterial, contain the bulk of the X-ray absorber within the particles.Any X-ray absorber on the surface of the particles can be washed off byartificial gastro-intestinal juice so that all X- ray absorber substanceis contained within the resin particles and withdrawn from thegastro-intestinal juices in the patients stomach and intestines. Thus,when using these methods of preparing the X-ray contrast medium it ispossible to use X-ray absorbers which because of their toxicity couldnot hitherto with safety be considered as components of X-ray contrastmedia. Thus the invention has made it possible to use bismuthsubcarbonate and thorium oxide as X-ray absorbers in X-ray contrastmedia for X-ray examination of the gastrointestinal tract.

Still another possibility of preparing the X-ray contrast mediumaccording to the invention is to prepare a solution of a volatile liquidand a film forming substance insoluble in the stomach comprising amember of the group consisting of shellac and cellulose acetatephthalate and to suspend the X-ray absorber in the solution. The foamedresin particles are then coated with the resultant mixture and thevolatile liquid driven off. Any X-ray absorber not contained in andcovered by the coating is removed eg. by washing with artificial gastricjuice. The coated particles are then suspended in a gel of water and athickening agent in such a quantity that the final X-ray contrast mediumhas a density of 0.8 to l.=l g./cm. This X-ray contrast medium isespecially suitable in the X-ray examination of the ventricle andesophagus.

When iodine is used as the X-ray absorber it is possible to incorporatethe absorber with the particulate res in foam by modifying the startingmonomer from which the resin is prepared. In this case the iodine ischemically bonded to the monomer in a first stage and then the monomeris polymerized in well known manner. This modified iodine containingresin in a third stage is expanded in a manner well known in the art toproduce particulate modified resin foam which is mixed with water andthe non-toxic thickening agent, the proportions of the particulatemodified resin foam, the water and the thickening agent being such thatthe final X-ray contrast iedium has a density of 0.8 to 1.1 g./cm.

As the particulate resin foam in the X-ray contrast medium of theinvention it is possible to use a polystyrene, polyethylene and urearesin. However, the preferred resins are the polystyrenes. All theseresins can be prepared by methods well known in the art.

As a non-toxic thickening agent for use in the X-ray contrast medium ofthe invention it is possible to use vegetable gums. water, solublecellulose esters and thickeners of seaweed origin e.g. alginates, agarsand carrageens.

Specific examples of thickening agents that have been used in X-raycontrast media of the invention are sodium alginate, potassium alginate,propylene glycol alginate, ammonium alginate, agar-agar, sodiumcarrageenate, potassium carrageenate, gum acacia, gum guar, gum locust,gum tragacanth, sodium carboxyl methyl cellulose, ethyl hydroxy ethylcellulose and methyl cellulose.

The following examples will serve to illustrate the invention withoutlimiting the same. In these examples all percentages and ratios refer topercentages and ratios by weight.

Example 1 Foamed polystyrene particles prepared in a known manner andhaving a diameter of about 0.5 mm. and a bulk density of about 0.1 to0.2 g./cm. were stirred into a 1% sodium alginate solution in water toprovide them with a coating of sodium alginate. The particles were thenremoved from the sodium alginate solution and washed with water.Thereafter, the coated particles were suspended in a 0.1 N calciumchloride solution in water. Excess calcium chloride solution was allowedto drain off. In the meantime, barium sulphate (grade U.S.P.) had beensuspended in the remainder of the original sodium alginate solution, andinto this suspension the coated particles treated with calcium chloridewere suspended. The calcium ions act as a stabilizer for the sodiumalginate coating of the polystyrene particles and thus prevent thesuspended barium sulphate and polystyrene particles from separating toorapidly when the X-ray contrast medium passes through thegastro-intestinal tract. The relative amounts of the ingredients werechosen in such a way that the final X-ray contrast medium had a bulkdensity of about 0.95 to 1.05 g./cm. Since the density of the X-raycontrast medium was about the same as that of the organs in theabdominal cavity the X-ray contrast medium could pass rapidly throughthe stomach, the small intestine and large intestine in aphysiologically correct way without it being necessary for the patientto be in a recumbent position and without any extraneous influence bypressure or turning of the patient. The X-ray contrast medium spreadsuccessively and in a thin even layer over the inner surfaces of theorgans.

Example 2 The preparation of the X-ray contrast medium was carried outas described in Example 1 except that foamed polyethylene particles witha diameter of about 0.5 mm. and ammonium alginate were used instead ofthe poly styrene particles and the sodium alginate, respectively. Theresulting X-ray contrast medium was found to act in a physiologicallycorrect way when passing through the stomach, the small intestine andthe large intestine, whereby the barium sulphate suspension spreadsuccessively and was distributed in a thin even layer over the innersurfaces of the organs.

Example 3 A 10 to 15% alcoholic solution of schellac or celluloseacetate phthalate was prepared. In this solution barium sulphate wassuspended. Spherical foamed polystyrene particles having a diameter ofabout 0.1 mm. and prepared in a manner well known in the art were addedto the suspension under stirring in such a quantity that the ratio ofpolystyrene particles to barium sulphate was about 1:2.5 by Weight. Theformation of large conglomerates of particles was prevented by means oftalc or colloidal silica. Thereafter the material was dried and sievedand any unabsorbed barium sulphate was removed. The polystyreneparticles thus coated with barium sulphate incorporated in a shellac orcellulose acetate phthalate layer were suspended in a 1% solution ofethyl hydroxy ethyl cellulose in water in such a quantity, that thefinal X-ray contrast medium had a density of about 0.8 to 1.1 g./cm. TheX-ray contrast medium prepared in this way was found to be an excellentX-ray contrast medium for the X-ray examination of the gastro-intestinaltract.

Example 4 Example 3 was repeated except that thorium oxide wassubstituted for the barium sulfate and that gum tragacanth wassubstituted for the ethyl hydroxy ethyl cellulose. The final X-raycontrast medium having a density of about 0.8 to 1.1 g./cm. was found tobe an excellent X-ray contrast medium in the X-ray examination of thegastrointestinal tract.

Example 5 100 g. polystyrene were dissolved in 300 ml. ethyl acetate.The solution was filtered and 200 g. bismuth subcarbonate were stirredinto the filtrate. The solution was homogenized and spread in a thinlayer on a polyethylene foil, where it was allowed to dry. After dryingthe material was ground in a mill with rotating knives until thematerial passed through a 50 mesh sieve (U.S. standard sieve). Thepowder was covered with petroleum ether and was allowed to stand forabout 12 hours during which it was occasionally stirred. Afterwardsexcess petroleum ether was sucked off and the powder was sieved througha coarse sieve into water having a temperature of about C. and in whichthe powder was vigorously stirred. The powder particles were therebyexpanded and then they were immediately removed from the hot water,rinsed in cold water, dried and aired for some days. 50 g. of thismaterial were stirred in about ml. of a 1% solution of sodiumcarrageenate in water. The material thus prepared was an excellent X-raycontrast medium in X-ray examination of the gastro-intestinal tract.

Example 6 Example 5 was repeated except that thorium oxide wassubstituted for the bismuth subcarbonate. The final suspension was foundto be an excellent X-ray contrast medium in X-ray examination of thegastrointestinal tract.

Example 7 100 g. of a mixture of ortho and para iodine styrene monomerwere polymerized in some well known manner e.g. through storing themonomer at 60 C. for a few hours with a small quantity ofbenzoylperoxide added. The obtained product containing 55% iodine wascrushed into small particles and expanded as described in Example 5. Theexpanded iodine-containing resin particles were stirred into a 1%solution of methyl cellulose in water in such a quantity that the finalproduct had a density of 0.95 to 1.05 g./cm. This product could be usedas an X-ray contrast medium in X-ray examination of thegastro-intestinal tract.

Example 8 100 g. barium sulphate were thoroughly mixed into 50 g. of aurea resin premix. A curing agent solution was added and the mixture waswhipped to obtain a foam with small homogeneous cells. After curing theproduct was ground and sieved and the fraction with a particle sizebetween 0.1 and 0.5 mm. was used. This fraction was mixed with a 1%solution of potassium carrageenate in water in such a quantity that thefinal X-ray contrast medium had a density of 0.8 to 1.1 g./cm. ThisX-ray contrast medium was suitable for use in X-ray examination of thegastro-intestinal tract.

Example 9 100 g. polyethylene granules prepared in a known manner andcontaining an incorporated organic blowing agent were mixed with 100 g.barium sulphate. This material was extruded in thin sheets which duringthe extrusion expanded to a cellular product. This product wascomminuted into particles about 0.5 mm. in diameter and was used inpreparing an X-ray contrast medium by stirring the particles into anagar-agar gel in such a quantity that the final X-ray contrast mediumhad a density of about 0.95 to 1.05 g./cm. This X-ray contrast mediumwas suitable for use in X-ray examination of the gastrointestinal tract.

The foregoing detailed description has been given for the purposes ofillustration only and is not intended to limit the scope of the presentinvention which is to be determined from the appendant claims.

What we claim and desire to secure by Letters Patent 1s:

1. An X-ray contrast medium comprising an X-ray absorber comprising amember of the group consisting of barium sulphate, bismuth subcarbonate,thorium oxide and iodine, a particulate, therapeutically acceptableresin foam comprising a member of the group consisting of polystyrenes,polyethylenes and urea resins, water, and at most 1% based on the X-raycontrast medium of a non-toxic thickening agent of the group consistingof thickeners of seaweed origin, vegetable gums and water solublecellulose esters, the proportions of said components being such that theX-ray contrast medium has a density of 0.8 to 1.1 g./cm

2. The X-ray contrast medium according to claim 1, in which theproportions of said components are such that the X-ray contrast mediumhas a density of 0.95 to 1.05 g./cm

3. An X-ray contrast medium comprising a particulate, therapeuticallyacceptable resin foam comprising a member of the group consisting ofpolystyrenes, polyethylenes and urea resins, an X-ray absorbercomprising a member of the group consisting of barium sulphate, bismuthsubcarbonate, thorium oxide and iodine, said X-ray absorber beinghomogeneously incorporated in said particulate resin foam, water and atmost 1% based on the X-ray contrast medium of a non-toxic thickeningagent of the group consisting of thickeners of seaweed origin, vegetablegums and water soluble cellulose esters, the proportions of saidcomponents being such that the X-ray contrast medium has a density of0.8 to 1.1 g./cm.

4. The X-ray contrast medium according to claim 3, wherein said X-rayabsorber is barium sulphate and said resin foam is a polystyrene.

5. An X-ray contrast medium comprising a particulate, therapeuticallyacceptable polystyrene resin foam, iodine chemically bonded to saidresin, water and at most 1% based on the X-ray contrast medium of anon-toxic thickening agent of the group consisting of thickeners ofseaweed origin, vegetable gums and water soluble cellulose esters, theproportions of said components being such that the X-ray contrast mediumhas a density of 0.8 to 1.1 g./cm.

6. An X-ray contrast medium comprising an X-ray absorber comprising amember of the group consisting of barium sulphate, bismuth subcarbonate,and thorium oxide, a particulate, therapeutically acceptable resin foamcomprising a member of the group consisting of polystyrenes,polyethylenes and urea resins, said particulate resin foam being coatedwith said X-ray absorber, water and at most 1% based on the X-raycontrast medium of a non-toxic thickening agent of the group consistingof thickeners of seaweed origin, vegetable gums and Water solublecellulose esters, the proportions of said components being such that theX-ray contrast medium has a density of 0.8 to 1.1 g./cm.

7. An X-ray contrast medium comprising a particulate, therapeuticallyacceptable resin foam comprising a member of the group consisting ofpolystyrenes, polyethylenes and urea resins, an X-ray absorbercomprising a member of the group consisting of barium sulphate, bismuthsubcarbonate, and thorium oxide, a film forming substance insoluble inthe stomach comprising a member of the group consisting of shellac andcellulose acetate phthalate, said film forming substance substantiallycovering each particle of said particulate resin foam and said X-rayabsorber being distributed in and covered by said film formingsubstance, water and at most 1% based on the X-ray contrast medium of anon-toxic thickening agent of the group consisting of thickeners ofseaweed origin, vegetable gums and water soluble cellulose esters, theproportions of said components being such that the X-ray contrast mediumhas a density of 0.8 to 1.1 g./cm.

References Cited FOREIGN PATENTS 657,979 10/1951 Great Britain 16795ELBERT L. ROBERTS, Primary Examiner.

LEWIS GOTTS, Examiner.

R. L. H-UFF, Assistant Examiner.

1. AN X-RAY CONTRAST MEDIUM COMPRISING AN X-RAY ABSORBER COMPRISING AMEMBER OF THE GROUP CONSISTING OF BARIUM SULPHATE, BISMUTH SUBCABONTE,THORIUM OXIDE AND IODINE, A PARTICULATE, THERAPEUTICALLY ACCEPTABLERESIN FOAM COMPRISING A MEMBER OF THE GROUP CONSISTING OF POLYSTYRENES,POLYETHYLENES AND UREA RESINS, WATER, AND AT MOST 1% BASED ON THE X-RAYCONTRAST MEDIUM OF A NON-TOXIC THICKENING AGENT OF THE GROUP CONSISTINGOF THICKENERS OF SEAWEED ORIGIN, BEGETABLE GUMS AND WATER SOLUBLECELLULOSE ESTERS, THE PROPORTION OF SAID COMPONENTS BEING SUCH THAT THEX-RAY CONTRAST MEDIUM HAS A DENSITY OF 0.8 TO 1.1 G./CM3.